Lorcaserin

Lorcaserin, marketed under the brand name Belviq[3][4] is a weight-loss drug developed by Arena Pharmaceuticals. It reduces appetite by activating a type of serotonin receptor known as the 5-HT2C receptor in a region of the brain called the hypothalamus, which is known to control appetite.[5] It was removed from the market in the United States in 2020 due to an increased risk of cancer detected in users of Belviq. [6][1]

Lorcaserin
Clinical data
Trade namesBelviq
Other namesAPD-356
AHFS/Drugs.comMonograph
MedlinePlusa613014
License data
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • US: Schedule IV / Withdrawn[1]
Pharmacokinetic data
Protein binding70%[2]
MetabolismHepatic (extensive)[2]
Elimination half-life11 hours[2]
ExcretionRenal (92.3%), Faecal (2.2%)[2]
Identifiers
IUPAC name
  • (1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.237.138
Chemical and physical data
FormulaC11H14ClN
Molar mass195.69 g·mol−1
3D model (JSmol)
SMILES
  • CC1CNCCC2=C1C=C(C=C2)Cl
InChI
  • InChI=1S/C11H14ClN/c1-8-7-13-5-4-9-2-3-10(12)6-11(8)9/h2-3,6,8,13H,4-5,7H2,1H3/t8-/m0/s1 Y
  • Key:XTTZERNUQAFMOF-QMMMGPOBSA-N Y
  (verify)

Medical uses

Lorcaserin is used long term for weight loss in those who are obese.[7]

Side effects

In December 2012, the US Drug Enforcement Administration proposed classifying lorcaserin as a Schedule IV drug because it has hallucinogenic properties at higher than approved doses and users could develop psychiatric dependencies on the drug.[8][9] On 7 May 2013, the US Drug Enforcement Administration classified lorcaserin as a Schedule IV drug[10] under the Controlled Substances Act.[8]

There has been concern that lorcaserin can cause cardiac valvulopathy based upon the reports of subjects taking the drug in Phase 2 trials. However, a Phase 3 clinical trial of the drug was conducted and the results published in the October 2014 Postgraduate Medicine journal, a peer-reviewed medical journal for physicians. These results found no statistically significant differences in valvulopathy rates compared to control, being 2.4% for the drug subjects and 2.0% for controls, and concluded that the drug is safe for the target population[11][12] although more long-term data is needed.[13]

A drug safety communication from the US Food and Drug Administration (FDA), in January 2020, stated that a clinical trial demonstrated a possible increased risk of cancer for those taking lorcaserin.[14] The FDA approval of lorcaserin required the manufacturer to conduct a randomized, double-blind, placebo-controlled clinical trial to evaluate the risk of heart-related problems.[14] The trial was conducted in approximately 12,000 participants over five years and more patients taking lorcaserin were diagnosed with cancer compared to patients taking placebo.[14]

In February 2020, the FDA requested that the manufacturer lorcaserin voluntarily withdraw the drug from the US market because a safety clinical trial showed an increased occurrence of cancer. The drug manufacturer, Eisai, has submitted a request to voluntarily withdraw the drug.[15]

Mechanism of action

Lorcaserin is a selective 5-HT2C receptor agonist,[16][17] and in vitro testing of the drug showed reasonable selectivity for 5-HT2C over other related targets.[18][19][20] 5-HT2C receptors are located almost exclusively in the brain, and can be found in the choroid plexus, cortex, hippocampus, cerebellum, amygdala, thalamus, and hypothalamus. The activation of 5-HT2C receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss through satiety.[21] This hypothesis is supported by clinical trials and other studies. While it is generally thought that 5-HT2C receptors help to regulate appetite as well as mood, and endocrine secretion,[22] the exact mechanism of appetite regulation is not yet known. Lorcaserin has shown 100x selectivity for 5-HT2C versus the closely related 5-HT2B receptor, and 17x selectivity over the 5-HT2A receptor.[23][24]

Receptor[2]EC50 [nM]Ki[nM]
5-HT2C3913
5-HT2B2380147
5-HT2A55392

Approval history

On 22 December 2009, a New Drug Application (NDA) was submitted to the Food and Drug Administration (FDA) in the United States.[25] On 16 September 2010, an FDA advisory panel voted 9–5 against approval of the drug based on concerns over both efficacy and safety, particularly the findings of tumors in rats.[26][27] On 23 October 2010, the FDA decided not to approve the drug based on the available data. This was not only because cancer promoting properties could not be ruled out, but also because the weight loss efficacy was considered "marginal."[28]

On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes.[29] On 27 June 2012, the FDA approved lorcaserin for use in adults with a body mass index (BMI) of 30 or greater (obese), or adults with a BMI of 27 or greater (overweight) and who have at least one weight-related condition such as high blood pressure (hypertension), type 2 diabetes, or high cholesterol (dyslipidemia).[3][30]

The safety and efficacy of Belviq were evaluated in three randomized, placebo-controlled trials that included nearly 8,000 obese and overweight patients, with and without type 2 diabetes, treated for 52 to 104 weeks.[3] All participants received lifestyle modification that consisted of a reduced calorie diet and exercise counseling.[3] Compared with placebo, treatment with Belviq for up to one year was associated with average weight loss ranging from 3 percent to 3.7 percent.[3]

About 47 percent of patients without type 2 diabetes lost at least 5 percent of their body weight compared with about 23 percent of patients treated with placebo.[3] In people with type 2 diabetes, about 38 percent of patients treated with Belviq and 16 percent treated with placebo lost at least 5 percent of their body weight.[3] Belviq treatment was associated with favorable changes in glycemic control in those with type 2 diabetes.[3] The approved labeling for Belviq recommends that the drug be discontinued in patients who fail to lose 5 percent of their body weight after 12 weeks of treatment, as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment.[3]

The drug's manufacturer was required to conduct six postmarketing studies, including a long-term cardiovascular outcomes trial to assess the effect of Belviq on the risk for major adverse cardiac events such as heart attack and stroke.[3]

On July 15, 2016, the extended release version of lorcaserin was approved for use in the United States.[31]

References
  1. "FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market". U.S. Food and Drug Administration (FDA). 14 January 2020. Retrieved 1 April 2020.
  2. "Belviq (lorcaserin hydrochloride) tablet [Eisai, Inc]". DailyMed. Eisai, Inc. August 2012. Archived from the original on 21 October 2013. Retrieved 21 October 2013.
  3. "FDA approves Belviq to treat some overweight or obese adults". U.S. Food and Drug Administration (FDA) (Press release). 27 June 2012. Archived from the original on 1 September 2012. Retrieved 14 January 2020. This article incorporates text from this source, which is in the public domain.
  4. "Belviq". Trademarkia. 23 June 2011. Archived from the original on 30 June 2012. Retrieved 27 June 2012.
  5. Shukla AP, Kumar RB, Aronne LJ (2015). "Lorcaserin Hcl for the treatment of obesity". Expert Opinion on Pharmacotherapy. 16 (16): 2531–8. doi:10.1517/14656566.2015.1096345. PMID 26472579.
  6. "Belviq, Belviq XR (lorcaserin) by Eisai: Drug Safety Communication - FDA Requests Withdrawal of Weight-Loss Drug". U.S. Food and Drug Administration (FDA). 13 February 2020. Retrieved 18 February 2020.
  7. Bray GA, Frühbeck G, Ryan DH, Wilding JP (May 2016). "Management of obesity". Lancet. 387 (10031): 1947–56. doi:10.1016/S0140-6736(16)00271-3. PMID 26868660.
  8. Wilson MR (19 December 2012). "Reg Watch". The Hill. Archived from the original on 20 March 2013.
  9. "Schedules of Controlled Substances: Placement of Lorcaserin into Schedule IV". 19 December 2012.
  10. "Department Of Justice Drug Enforcement Administration 21 CFR Part 1308, Placement of Lorcaserin into Schedule IV". 8 May 2013.
  11. Greenway FL, Shanahan W, Fain R, Ma T, Rubino D (October 2016). "Safety and tolerability review of lorcaserin in clinical trials". Clinical Obesity (Review). 6 (5): 285–95. doi:10.1111/cob.12159. PMID 27627785.
  12. "BELVIQ and BELVIQ XR HCP Home Page". www.belviqhcp.com. Archived from the original on 16 June 2016.
  13. Patel DK, Stanford FC (March 2018). "Safety and tolerability of new-generation anti-obesity medications: a narrative review". Postgraduate Medicine (Narrative review). 130 (2): 173–182. doi:10.1080/00325481.2018.1435129. PMC 6261426. PMID 29388462.
  14. "Safety clinical trial shows possible increased risk of cancer with weight-loss medicine Belviq, Belviq XR (lorcaserin)". U.S. Food and Drug Administration (FDA). 14 January 2020. Retrieved 14 January 2020. This article incorporates text from this source, which is in the public domain.
  15. "FDA In Brief: FDA Requests Voluntary Withdrawal of Weight-Loss Medication After Clinical Trial Shows an Increased Occurrence of Cancer". FDA. 13 February 2020.
  16. Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, et al. (May 2008). "Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization". The Journal of Pharmacology and Experimental Therapeutics. 325 (2): 577–87. doi:10.1124/jpet.107.133348. PMID 18252809.
  17. Zhu Q, Wang J, Bian X, Zhang L, Wei P, Xu Y (September 2015). "Novel synthesis of antiobesity drug lorcaserin hydrochloride". Organic Process Research & Development. 19 (9): 1263–1267. doi:10.1021/acs.oprd.5b00144.
  18. US patent 6953787, Smith B, Smith J, "5HT2c receptor modulators", published 2003-10-04, issued 2005-11-10
  19. US patent 7704993, Smith B, Gilson III CA, Schultz J, Smith J, "Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases", published 2004-16-06, issued 2010-27-04
  20. US patent 8207158, Smith B, Smith J, "5HT2c receptor modulators", published 2011-27-05, issued 2012-26-06
  21. Spreitzer H (13 September 2010). "Lorcaserin". Österreichische Apothekerzeitung (in German). 64 (19): 1083.
  22. Millan MJ (2005). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies". Therapie. 60 (5): 441–60. doi:10.2515/therapie:2005065. PMID 16433010. Archived from the original on 28 August 2015.
  23. Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, et al. (March 2005). "Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity". Bioorganic & Medicinal Chemistry Letters. 15 (5): 1467–70. doi:10.1016/j.bmcl.2004.12.080. PMID 15713408.
  24. Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, et al. (January 2008). "Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity". Journal of Medicinal Chemistry. 51 (2): 305–13. doi:10.1021/jm0709034. PMID 18095642.
  25. "Lorcaserin New Drug Application". Drugs.com. 22 December 2009. Archived from the original on 3 March 2016.
  26. Pollack A (16 September 2010). "F.D.A. Panel Rejects Diet Pill". The New York Times. Archived from the original on 17 July 2011.
  27. Pollack A (16 September 2010). "F.D.A. Panel Urges Denial of Diet Drug". The New York Times. Archived from the original on 22 August 2017.
  28. "FDA Issues Complete Response Letter for Lorcaserin New Drug Application". 23 October 2010. Archived from the original on 24 October 2010.
  29. "New Diet Drug Lorcaserin Wins Vote From FDA Panel". webmd. 10 May 2012. Archived from the original on 12 May 2012.
  30. "Drug Approval Package: Belviq (lorcaserin hydrochloride) Tablets NDA #022529". U.S. Food and Drug Administration (FDA). 7 August 2012. Retrieved 14 January 2020.
  31. "Belviq XR (lorcaserin hydrochloride) extended-release tablets". U.S. Food and Drug Administration (FDA). 26 October 2016. Retrieved 14 January 2020.
  • "Lorcaserin". Drug Information Portal. U.S. National Library of Medicine.
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